In an attempt to discover analogs of the prototype anticonvulsant methyl 4-[(4'-chlorophenyl)-amino]-6-methyl-2-oxo-3-cyclohexene-1-carboxylate, 1, alkyl 4-[(5'-chloro-2'-pyridinyl)amino]-6-methyl-2-oxo-3-cyclohexene-1-carboxyla tes, 2 [R.dbd.CH.sub.3 (2a); R.dbd.C.sub.2 H.sub.5 (2b)], and alkyl 4-[(5'-methyl)-3'-isoxazolylamino]-6-methyl-2-oxo-3-cyclohexene-1-carboxyl ates, 3 [R.dbd.CH.sub.3 (3a); R.dbd.C.sub.2 H.sub.5 (3b); R.dbd.C(CH.sub.3).sub.3 (3c)], have been targeted. Edafiogho, I. O.; Hinko, C. N.; Chang, H.; Moore, J. A.; Mulzac, D.; Nicholson, J. M.; Scott, K. R. Synthesis and anticonvulsant activity of enaminones. J. Med. Chem. 1992, 35, 2798-2805. Scott, K. R.; Edafiogho, I. O.; Richardson, E. L.; Farrar, V. A.; Moore, J. A.; Tietz, E. I.; Hinko, C. N.; Chang, H.; El-Assadi, A; Nicholson, J. M. Synthesis and anticonvulsant activity of enaminones. 2. Further structure activity correlations. J. Med. Chem. 1993, 36, 1947-1955. U.S. Pat. No. 5,580,894. ##STR2##
Moreover, the basic phenothiazine ring system has been shown to be an essential pharmacophore for tranquilizers, anticancer agents, antiinflammatory agents, antihistaminics, anthelminics, local anesthetics, antiseptics, growth inhibitors, and in the treatment of neuropsychiatric disorders. (a) Gupta, R. R. Ed. Phenothiazines and 1,4-benzothiazines. Chemical and biomedical aspects. Elsevier, Amsterdam, The Netherlands, 1988. (b) Benz, G.; Fengler, G.; Meyer, H.; Niemers, E.; Fiedler, V.; Mardin, M.; Mayer, D.; Perzbom, E.; Seuter, F. et al. Use of 4H-1,4-benzothiazines in the prevention and therapy of respiratory diseases, inflammations/rheumatism, thromboembolic diseases, ischemias and infarctions, heart rhythm disturbances, arteriosclerosis, and dermatosis, drugs for this purpose, and active substances contained in these drug. Chem. Abstr. 1986, 105, 60620y; Ger. Offen. DE 3,426,564. (c) Niemers, E.; Gruetzmann, R.; Mardin, M.; Busse, W. D.; Meyer, H. Annellated 4H-1,4-benzothiazine lipoxygenase inhibitors. Chem. Abstr. 1984, 100, 185787k; Ger. Offen. DE 3,229,122. The mechanism for the variety of therapeutic activities is believed to be due to the presence of a fold along the nitrogen-sulfur axis. Gupta, R. R.; Saraswat, V.; Gupta, V.; Rajoria, C. M.; Gupta, A.; Jain, M. Synthesis of 5,6- and 5,7-dichloro-3-methyl-4H-1,4-benzothiazines and their conversion into sulfones. J. Heterocyclic Chem. 1993, 30, 803-806. Anticonvulsant activity has been reported for a related series of 2,3-dihydro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitriles. Chorvat, R. J.; Desai, B. N.; Radak, S. E.; Bloss, J.; Hirsch, J.; Tenen, S. Synthesis, benzodiazepine receptor binding, and anticonvulsant activity of 2,3-dihydro-3-oxo-5H-pyrido-[3,4-b][1,4]benzothiazine-4-carbonitriles. J. Med. Chem. 1983, 26, 845-850.